Immune-mediated thrombocytopenias are the leading cause of hemorrhagic diathesis, the prevalence being greater than 1 per 2,000. Autoimmune idiopathic thrombocytopenic purpura (ITP) is the most common type. Sensitizing antigens (Ags) in ITP have not been defined and most serologic tests for antiplatelet antibodies (Abs) have been insensitive or nonspecific. We developed an assay for Abs against major platelet membrane glycoproteins (GPs) and their peptide derivatives which detected Abs in 85% of 47 ITP patients, defined the classes and affinities of Abs, and determined percentage of cytoplasmic versus external membrane epitopes involved in sensitization. Posttransfusion purpura (PTP) is a rare disorder occurring 5-7 days after transfusions containing platelet material. Patients' plasmas contain an alloAb against a platelet Ag lacking in the patient but present in transfused blood. Reasons for destruction of autologous platelets have been obscure. We have now shown that there are platelet-derived membrane Ags in normal donor plasma that, when transfused, elicit alloAbs that adsorb to recipients' platelets as Ag-Ab complexes and cause platelet destruction. We developed a guinea pig model to reproduce this disease and have used electron microscopy to identify the platelet microparticles. Occurrence of phagocytosis in immune platelet destruction is controversial. We studied metabolic responses of monocytes armed with antiplatelet auto- and allo-Abs and exposed to appropriate platelet Ags for indications that monocytes may participate in immune platelet destruction. Arachidonate metablites including thromboxanes, leukotrienes, and prostaglandin E2 were increased in monocytes armed with antibodies from ITP or PTP patients and then exposed to platelet-specific Ags, suggesting that cellular immunity plays a role in immune thrombocytopenia. Among patients referred with platelet dysfunction, 3 had unique Abs causing hemorrhage by interfering with the RGD binding site of the integrin, GPIIb/IIIa. A patient with drug hemolytic anemia had antibodies reactive with band 3 which is the first time a specific red cell membrane protein has been implicated in this syndrome.